The goal of this study is to determine the role of xenobiotic metabolic pathways in DEP enhancement of allergic inflammation. DEPs mediate the majority of their pro-allergenic effects by virtue of the organic chemicals they contain, probably through generation of reactive oxygen species and oxidative stress. We will study the genes and pathways involved in the detoxification of these chemicals and their involvement in DEP-enhancement of allergic responses. PAHs bind to the cytosolic AHR resulting in induction of Phase I enzymes. Other DEP chemicals (quinones) can alter the redox state of the cells and induce Phase II enzymes. These pathways are linked by the ability of Phase I enzymes to convert PAHs to oxygenated PAHs (oxy-PAHs), which also induce Phase II enzymes. We will study the capacity of Phase I and II enzymes to regulate DEP-induced primary and secondary allergic responses. Phase I and II enzymes may have opposing effects on allergic endpoints. Phase I enzymes may increase the amount of oxy-PAH generating ROS, oxidative stress and ultimately allergic inflammation, while Phase II enzymes may detoxify oxy-PAH and reduce oxidative stress and thereby lessen DEP-enhanced allergic inflammation. Specific Aim 1 will test the hypothesis that DEP effects are mediated by the AHR and Phase I enzymes. We will test whether aromatic hydrocarbons that bind the AHR and increase expression of Phase I enzymes enhance allergic inflammation in a murine asthma model. We will also test whether there is modulation of DEP-induced allergic inflammation in AHR-deficient (knockout) mice and mice deficient in the key Phase I enzyme CYPIAI. Specific Aim 2 will test the hypothesis that DEP effects on allergic inflammation mediated by oxidative stress are modulated by Phase II enzymes. We will test the general principle that alleviation of DEP-induced oxidative stress by antioxidants protects mice from DEP-induced allergic inflammation. We will also test whether DEP-induced allergic inflammation is modulated in mice deficient in Nrf2, a transcription factor that controls regulation of Phase II enzymes or in mice deficient in an important Phase II enzyme, NQOI. Specific Aim 3 will test the hypothesis that polymorphisms in human Phase II enzyme genes increase the susceptibility of individuals to respond to the immune enhancing effects of DEP, and using our established human nasal mucosal challenge model of DEP-induced allergic responses, we will test the effects of two key Phase II enzyme genes polymorphisms (NQOI and GSTMI) on the inter-individual variability susceptibility to DEP.